Asthma associated morbidity, disability and rates of premature death continue to increase. Asthma is now recognized as a disease of airway inflammation in which airway eosinophilia is a prominent histologic feature. Eosinophils in asthmatic airways are activated and release preformed toxic cationic granule proteins; they generate oxidative products, lipid mediators and pro-inflammatory cytokines that can induce airway hyperresponsiveness which is the cardinal physiological feature of asthma. The importance of airway eosinophilia to asthma is suggested by the observation that the efficacy of steroids in the treatment of asthma is associated with the resolution of airway eosinophilia. Clarifying the mechanisms that recruit eosinophils into the airway has the potential to identify novel therapeutic targets relevant to allergic disease. Modulation of the eosinophilic inflammatory response might result in more effective immunotherapy without the toxicity associated with corticosteroid therapy. Our long term goals are to understand the role of eotaxin in airway inflammation and eosinophil tracking, which may lead to the development of novel asthma therapies. We propose to determine if eotaxin is a sufficient and necessary stimulus for eosinophil homing and airway hyperresponsiveness in murine models of allergic airways disease. These 'proof of concept' studies in the mouse, aimed at determining if blocking eotaxin function is a viable approach for a novel asthma therapy, will be coupled to human studies aimed at establishing a link between eotaxin and asthma. We specifically propose: (1) To characterize the biological properties of eotaxin in-vitro and in- vivo, including studying the role of eotaxin in mediating nasal and airway eosinophilia and bronchial hyperreactivity by administering purified, active, recombinant eotaxin to mice. (2) To determine if neutralizing eotaxin will prevent eosinophil migration and airway hyperactivity by generating a neutralizing hamster anti-mouse eotaxin monoclonal antibody. (3) To correlate the expression of eotaxin mRNA and protein in the lungs and bronchoalveolar lavage fluid following allergen challenge in allergic patients with and without asthma. (4) To complete the characterization of the binding and signaling properties of the eotaxin receptor and to determine if it and/or a novel eosinophil seven transmembrane-spanning receptor (ESTR) is involved with the expression of the asthma phenotype in humans. This work will lead to a greater understanding of the importance of eotaxin and eosinophil receptors in asthma. In addition, we hope this work will elucidate the role of the eosinophil in inducing bronchial hyperreactivity in allergic diseases, as well as suggest potential targets for novel therapeutic interventions.